Type IV collagen is a distinctive glycoprotein which occurs almost exclusively in basement membranes. It differs from the other types of collagen, which are found mainly in interstitial connective tissue, with regard to several structural properties. See New Trends in Basement Membrane Research, K. Kuehn et al., eds., Raven Press, N.Y. (1982) at pages 57-67. It has a molecular weight (MW) of about 500,000 and consists of three polypeptide chains: two .alpha.1 (MW 185,000) chains and one .alpha.2 (MW 170,000) chain. Type IV collagen has two major domains: a large, globular, non-collagenous, NC1 domain and another major triple-helical, collagenous domain. The latter domain is only partially short, non-collagenous sequences. The amino acid sequence of this collageous domain is only partially known; however, the sequences of both the .alpha.1- and .alpha.2-chains of the non-collagenous NC1 domain is known. See U. Schwartz-Magdolen et al., FEBS Letters, 208, 203 (1986), and references cited therein. A diagrammatic representation of the type IV collagen molecule is shown in FIG. 1. Apparently, type IV collagen is a very complex and multidomain protein with different biological activities residing in different domains.
Type IV collagen is an integral component of basement membranes because it self-assembles to higher forms which make up the supportive matrix of these structures. Various other macromolecular components of basement membranes are thought to assemble on this supportive framework. For example, laminin, nidogen and haparan sulfate proteoglycan have been reported to bind to type IV collagen. Laminin was observed to bind to two distinct sites along the length of the helix-rich, collagenous domain of type IV collagen. Nidogen and heparan sulfate proteoglycan were observed to bind specifically to the non-collagenous NC1 domain. Another property of type IV collagen is the ability to self-assemble by end-to-end and lateral associations, as mentioned hereinabove. The end-product of the polymerized structure is an irregular polygonal network. The NC1 domain is required for network formation because it binds along the length of the helix-rich domain and brings adjacent molecules together, thus initiating lateral assembly. In the absence of lateral assembly, only end-to-end associations occur and the network-structure cannot be formed.
An additional function of type IV collagen is the binding to various cell types via cell surface receptors [M. Kurkinen et al., J. Biol. Chem., 259, 5915 (1984)]. M. Kurkinen et al. have reported that a major surface receptor protein with a molecular weight of 47,000 mediates this binding in the case of mouse embryo parietal endodermal cells.
The variety of functions attributed to type IV collagen indicates that this protein is an important reactant in many diverse and clinically important processes such as basement membrane assembly, cell migration, wound healing, tumor cell metastasis, diabetic microangiopathy, vascular hypertrophy due to hypertension and several kidney diseases. For example, Goodpastures's syndrome, a disease characterized by hemoptysis and hematuria due to alveolitis and nephritis, respectively, is associated with the presence of and antibody to the NC1 domain of type IV collagen in the serum of all Goodpasture's patients. Another hereditary kidney disease, Aport's familial nephritis is apparently due to a genetic defect of the NC1 domain of type IV collagen. Finally, in diabetes mellitus, intact type IV collagen, as well as the helix-rich domains, are chemically modified and functionally impaired by the increased amounts of glucose in the plasma and in the immediate vicinity of the basement membranes, i.e., in the extracellular matrix.
In order to better understand the pathophysiology of these processes at a molecular level, there is a need to try to assign each of the biological activities that type IV collagen exhibits to a specific subdomain (i.e., NC1, helix-rich) or aligopeptide of type IV collagen. If this can be achieved, it may be possible to synthesize small peptides which can provide the basis for important pharmaceutical compositions.